Biochemical studies of a patient with ketoacidosis due to a deficiency of CoA transferase have resulted in the extended investigation of the role of beta-hydroxybutyrate and acetoacetate in developmental homeostasis. These studies focus on the regulatory factors involved in the production of ketone bodies by the neonatal liver and in their utilization by the developing rat brain. To elucidate the metabolic interrelationship between ketone bodies, carbohydrates, and amino acids, a combination of studies is proposed. Data will be obtained from experiments using dissociated primary brain cells explanted from fetal and neonatal animals, as well as from established lines of glial and neuroblastoma cells. The studies are designed to differentiate between the metabolic fate of ketone bodies in neurons and glia and in subcellular organelles such as synaptosomes and mitochondria. The effects of neurotransmitters on these processes will also be examined. In addition, the process of ketogenesis will be examined in isolated hepatocytes and mitochondria from fetal and neonatal rats in a series of in vitro precursor-product experiments. The developmental pattern of the antiketonemic response to glycerol and alanine will also be investigated and the factor(s) which regulate these processes will be determined in order to elucidate the mechanisms involved in the differential responses of these two antiketonemic agents. The results of these studies will add to our understanding of metabolic compartmentations in the brain and should help clarify some of the ambiguities surrounding the production of ketone bodies. In addition, these studies should also provide for better clinical approaches to ketotic hypoglycemia and diabetes in children.